DESCRIPTION (Applicant's Abstract): Nicotine is the drug responsible for the addictive properties of tobacco. Because gaseous molecules diffuse more rapidly than smoke particles, gaseous nicotine deposits more readily in the respiratory tract than does particle-phase nicotine: gaseous nicotine is much more available to the body than particle-phase nicotine. The partitioning of nicotine between tobacco smoke particles and the gas phase is therefore of critical importance in determining the addictive properties of tobacco. The addition of ammonia (NH3) and other pH-boosting bases to cigarette tobacco during manufacturing can affect the gas/particle partitioning of nicotine in favor of the gas phase by enhancing the proportion of the volatile "free-base" form of nicotine. Establishing the underlying chemistry will be of considerable value. Since many of the highly carcinogenic N-nitrosamines undergo the same type of gas/particle partitioning exhibited by nicotine, the carcinogenicity of tobacco smoke also likely depends on the gas/particle partitioning process. However, very little quantitative attention has been given to this process for either nicotine or the N-nitrosamines. This research will greatly improve our understanding of tobacco addiction and carcinogenicity: Aim l. Determine dependence of the gas/particle partitioning equilibrium constant (Kp) for nicotine on gaseous NH3 concentration and RH for partitioning to selected tobacco-smoke particulate materials; Aim 2. Determine the inherent acidity (carboxylic acid and phenolic acid content), and water-content as a function of RH, of the tobacco-smoke particulate materials discussed in Aim 1; Aim 3. Construct and refine a physical-chemical model for the pH-dependent gas/particle partitioning of nicotine and other compounds to tobacco-smoke particulate materials; Aim 4. Construct a physiologically-based pharmacokinetic (PBPK) model which can predict nicotine delivery kinetics from deposited tobacco smoke to pulmonary blood as a function of tobacco smoke chemistry; and Aim 5. Determine the Kp values for tobacco-smoke N-nitrosamines for partitioning to tobacco-smoke particulate materials as a function of pure-compound vapor pressure p (torr) and RH.